A Let-7 MicroRNA SNP in the KRAS 3'UTR Is Prognostic in Early-Stage Colorectal Cancer

• Published in: Clinical cancer research 2011-12, Vol.17 (24), p.7723-7731
• Main Authors: SMITS, Kim M, PARANJAPE, Trupti, NALLUR, Sunitha, WOUTERS, Kim A. D, WEIJENBERG, Matty P, SCHOUTEN, Leo J, VAN DEN BRANDT, Piet A, BOSMAN, Fred T, WEIDHAAS, Joanne B, VAN ENGELAND, Manon
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions - genetics; Aged; Antineoplastic agents; Biological and medical sciences; Cohort Studies; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gene Frequency; Genotype; Humans; Kaplan-Meier Estimate; Male; Medical sciences; MicroRNAs - genetics; Middle Aged; Mutation; Neoplasm Staging; Pharmacology. Drug treatments; Polymorphism, Single Nucleotide; Prognosis; Proportional Hazards Models; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins p21(ras); ras Proteins - genetics; Risk Assessment - statistics & numerical data; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-11-0990

Colorectal cancer (CRC) is a common cause of death worldwide. Tumor-node-metastasis-system stage is currently used to guide therapy decisions but lacks precision. Prognostic biomarkers are needed to refine stratification of patients for chemotherapy but validated biomarkers are not yet available. Recently, a SNP in a lethal-7 (let-7) miRNA complementary site (LCS6) in the KRAS 3'untranslated region was suggested to affect survival in metastatic CRC. Effects in early-stage CRC are however unknown. We studied KRAS-LCS6 genotype, hypothesizing that it might identify early-stage cases with a poor prognosis, and could potentially be used in therapy decision-making. We studied 409 early stage, 182 stage III, and 69 stage IV cases, and 1,886 subcohort members from the Netherlands Cohort Study. KRAS-LCS6 genotype was assessed with TaqMan PCR. Kaplan-Meier analyses or Cox regression were used to assess associations between genotype and CRC risk or cause-specific survival. Early-stage cases with the KRAS-LCS6 variant had a lower CRC risk (incidence-rate ratio 0.68; 95% CI: 0.49-0.94) and a better survival (log-rank P = 0.038; HR 0.46; 95% CI: 0.18-1.14). In patients with KRAS-mutated CRC carrying the KRAS-LCS6 variant, the better outcome was enhanced as no patients died of CRC (log-rank P = 0.017). In advanced patients, no clear association between genotype and CRC risk or survival was observed. Our results indicate that early-stage CRC cases with the KRAS-LCS6 variant have a better outcome. In advanced disease, the better outcome no longer exists. For early-stage patients, KRAS-LCS6 genotype combined with KRAS mutations merits validation as a prognostic biomarker and consideration in therapy decision-making.